Breaking barriers in the first-line Helicobacter pylori treatment: Chinese multicenter trial validates vonoprazan-based triple therapy

Abstract

The global burden of Helicobacter pylori infection continues to drive the need for effective, well-tolerated, and regionally adaptable eradication regimens. Recently Han et al presented compelling results from a multicenter randomized controlled trial in China, demonstrating the non-inferiority and potential superiority of vonoprazan (VPZ)-based triple therapy over the standard 14-day bismuth quadruple regimen. Both the 10-day and 14-day VPZ-amoxicillin-clarithromycin regimens achieved eradication rates exceeding 90% per protocol, with similar or fewer adverse events, suggesting improved patient tolerability. This study reinforces the potential of VPZ to overcome the limitations of proton pump inhibitor-based regimens, particularly in populations with CYP2C19 polymorphisms and increasing clarithromycin resistance. These findings also lend support to shortened treatment durations, which could enhance adherence and reduce antimicrobial exposure. These data highlight an important shift in the therapeutic landscape, positioning VPZ as a strong candidate for first-line empirical therapies. However, broader implementation requires careful consideration of local resistance patterns, drug accessibility, and pharmacoeconomic implications.

Key Words: Helicobacter pylori; First-line treatment; Vonoprazan; Triple therapy; Proton pump inhibitors

Core Tip: This editorial highlights a pivotal multicenter randomized controlled trial from China demonstrating that vonoprazan (VPZ)-based triple therapy achieves superior or non-inferior Helicobacter pylori eradication rates compared to standard bismuth quadruple regimens, even in high clarithromycin resistance regions. The 10-day VPZ-amoxicillin-clarithromycin regimen exceeded 90% per-protocol efficacy with fewer adverse events, offering a simplified, well-tolerated alternative aligned with global treatment goals. These findings underscore a shift in empirical first-line therapy and support the integration of VPZ into updated regional and international guidelines.

INTRODUCTION

Helicobacter pylori (H. pylori) remains one of the most prevalent chronic bacterial infections worldwide, contributing significantly to the global burden of peptic ulcer disease, gastric mucosa-associated lymphoid tissue lymphoma, and non-cardia gastric cancer. Although various national guidelines have adopted different first-line eradication protocols, most regimens remain rooted in proton pump inhibitor (PPI)-based strategies, often paired with bismuth and multiple antibiotics. However, as antibiotic resistance increases and patient adherence declines due to complex polypharmacy, the gastroenterology community is increasingly seeking simplified, effective, and tolerable treatment alternatives. Over the past decade, the treatment paradigm for H. pylori infection has undergone a profound shift driven largely by the emergence of vonoprazan (VPZ), a novel potassium-competitive acid blocker. Initially developed in Japan, VPZ demonstrated rapid, potent, and sustained gastric acid suppression, independent of cytochrome P450 2C19 metabolism. Recent study showed that VPZ effectively inhibits gastric acid secretion during eradication, with the time percentages of pH > 6 at 75.3% and 97.2% with median pH values of 7.4 and 7.8 on days 1 and 7[1]. This pharmacological profile offers key advantages over traditional PPIs, particularly in populations with a high prevalence of CYP2C19 polymorphisms and growing antimicrobial resistance[2-4].

CHINESE MULTICENTER TRIAL VALIDATES VPZ-BASED TRIPLE THERAPY

Early Japanese multicenter trials of VPZ-based triple therapy refined eradication estimates across subpopulations and antibiotic resistance profiles. Notably, Maruyama et al[5] demonstrated 95.8% intention-to-treat (ITT) eradication with 7-day VPZ-amoxicillin-clarithromycin (VAC) compared to 69.6% with lansoprazole triple therapy, whereas Sue et al[6] focused on clarithromycin-susceptible strains. Another finely planned retrospective single-center study in Japan demonstrated non-inferiority of empirical VAC compared with susceptibility-guided PPI-based regimens[7]. A meta-analysis by Jung et al[8] pooling ten Japanese studies with over 3000 participants reported an overall eradication rate of 91% for VAC vs 75% for PPI-based regimens (risk ratio = 1.17). These data prompted updates to national guidelines in Japan and catalyzed broader academic interests.

The year 2020 marked a turning point with the expansion of VPZ research to non-Japanese populations. A randomized trial in Thailand showed non-inferiority of 7-day VAC compared to 14-day omeprazole-based therapy[9], while a landmark phase III double-blind trial across the United States and Europe (n = 1046) confirmed VAC’s non-inferiority and superiority of VAC in clarithromycin-resistant strains (84% vs 78%)[10]. Rokkas et al[11] conducted the first global network meta-analysis, ranking VAC highest among eight major H. pylori eradication regimens (surface under the cumulative ranking approximately is 97%), and late it was confirmed by other network meta-analyses[12-15] (Table 1). A Korean systematic review further supported the efficacy of VPZ-based first-line triple therapy in East Asian populations[16]. The scope of VPZ research has expanded further to include real-world evidence and mechanistic studies. A large claims database study involving approximately 27000 patient-years demonstrated reduced healthcare utilization and retreatment rates among patients treated with VAC[17]. Mechanistic research has linked transcriptomic changes in H. pylori to the superior kill rates observed with VPZ-containing regimens[18]. A comprehensive updated meta-analysis by Chen et al[19] confirmed the efficacy across different regions; however, it included only one randomized controlled trial (RCT) conducted outside Asia. Simultaneously, dual therapy optimization and comparisons of 10-day vs 14-day regimens were pursued in non-inferiority designs in China[20,21], and bismuth quadruple regimens with VPZ were found to be non-inferior to their PPI-based counterparts in propensity-matched analyses[22].

Table 1 Surface under the cumulative ranking of the Helicobacter pylori eradication rate first-line treatment regimens analyzed in network meta-analyses, (%).

Ref.	Therapies	SUCRA
		Overall data	West	East Asia	West Asia
Rokkas et al[11], 2021	VPZ-triple therapy	92.4		94.1
	Bismuth quadruple therapy	33.2	44.7	50.5	2.4
	AMOX-dual therapy	4.7	15.2	15.2	31.5
Malfertheiner et al[12], 2022	VPZ-triple therapy1	89.6	80.6
	VPZ-dual therapy1	80.3	77.2
	Bismuth quadruple therapy1	78.4	82
	AMOX-dual therapy1	65.6	65.7
Liu et al[13], 2023	VPZ-triple therapy	92.6
	VPZ-triple therapy2	89.3
	VPZ-dual therapy	56.3
	VPZ-dual therapy2	56.3
Huang et al[14], 2024	VPZ-triple therapy/14 days	78.2
	VPZ-triple therapy/7 days	43.2
	VPZ-dual therapy/14 days	61.7
	VPZ-dual therapy/7 days	37.2
Jiang et al[15], 2024	VPZ-triple therapy/14 days	90.4
	VPZ-dual therapy/14 days	51.0

¹Data presented as pooled (weighted) eradication rate.

²Surface under the cumulative ranking values in patients with clarithromycin resistant strains.

SUCRA: Surface under the cumulative ranking; VPZ: Vonoprazan; AMOX: Amoxicillin.

Last two years, VPZ-containing triple therapy studies have increasingly focused on diverse geographic, clinical, and economic contexts. A trial conducted in Pakistan[23] confirmed higher cure rates and improved cost-effectiveness of VAC vs standard triple therapy; however, a trial in Egypt[24] demonstrated low eradication rates of the standard triple therapy and VAC (70% vs 79.2%; P = 0.777), indicating suboptimal efficacy of both treatment regimens. In China and Taiwan, a growing body of high-quality multicenter randomized trials has explored 10-day vs 14-day regimens, once-daily dosing, and alternative combinations including hybrid and reverse-sequential therapies, consistently reporting eradication rates above 90% in ITT and PP analyses[25-30]. Moreover, a breakthrough randomized trial in penicillin-allergic patients confirmed superior outcomes using VPZ-based quadruple therapy with doxycycline and metronidazole[31]. In addition to these efficacy studies, pharmacoeconomic evaluations have begun to quantify the cost-saving potential of VPZ[32,33].

In line with the studies in the World Journal of Gastroenterology, Han et al[34] presented a rigorously conducted, multicenter, RCT comparing VAC to the widely used 14-day bismuth-containing quadruple therapy in a Chinese population. These findings have the potential to significantly reshape empirical treatment paradigms for H. pylori eradication in China and beyond. The authors randomized 524 naive H. pylori-positive patients across 19 clinical centers in Shandong province to receive either 14-day bismuth-containing quadruple therapy, a 14-day VAC, or a 10-day VAC. The eradication rates in both the ITT and per-protocol (PP) analyses were impressive in the VAC groups. In the PP analysis, the eradication rates were 93.9% and 90.6% for the 14-day and 10-day VAC groups, respectively, both of which were significantly higher than the 81.4% observed in the bismuth-containing quadruple therapy group. Adverse events were comparable among the groups and were numerically lowest in the 10-day VAC arm.

This trial is one of the first large-scale, prospective, head-to-head comparisons of VPZ triple therapy vs bismuth-containing quadruple therapy in mainland China. This multicenter approach ensures broad generalizability across clinical practice settings, and the randomized controlled design with ITT and PP analyses provides high-level evidence. The efficacy of both the 14-day and 10-day VAC regimens exceeded the 90% PP threshold recommended for empirical therapy by the Maastricht VI/Florence Consensus[35]. Importantly, the 10-day regimen achieved non-inferiority with fewer pills and a lower adverse event rate, which may translate to better adherence and cost-effectiveness in real-world settings. Results of this study provide to the clinician a choice between two regimens which demonstrate similar efficacy, but different duration and number of pills which is an important for some patients. China has reported rising resistance rates to clarithromycin and metronidazole[36,37], both of which threaten the success of traditional regimens. The resistance rate is highly variable among different regions of the country[38], and a simple and universally effective regimen is urgently needed. Although antibiotic susceptibility testing was not performed in this study, VPZ-based regimens were expected to be active even in clarithromycin-resistant strains, as the trial was performed in Shandong province, where the highest rate of clarithromycin resistance (67.1%) in China was registered[36]. This therapeutic advantage makes VAC a strong empirical option in areas in which susceptibility testing is not routinely available. Current Chinese and global guidelines still endorse bismuth quadruple therapy as the preferred first-line treatment[39]. However, the complexity and adverse event burden of these regimens have long been acknowledged as barriers to adherence. Han et al’s data provide timely and compelling support for re-evaluating the first-line position of bismuth-free regimens, particularly in health systems seeking to simplify treatment and improve population-level eradication rates[34].

Despite the strength of this study, several limitations should be noted. First, the lack of resistance testing, while reflective of many real-world settings, prevents a detailed understanding of how local resistance patterns may influence VAC efficacy. However, population in which the study was performed characterized by very high resistance rate to clarithromycin, which may be an indirect sign that VAC can be effective in other geographical areas with high prevalence of resistance. Second, the exclusion of patients with severe comorbidities and gastrointestinal bleeding limits the extrapolation to high-risk populations. Finally, long-term follow-up is needed to assess cost-effectiveness metrics.

CONCLUSION

The study by Han et al[34] represents a critical step toward modernizing H. pylori treatment in China. By demonstrating the non-inferiority and superior simplicity of VPZ-based triple therapy, particularly in a shortened 10-day course, this study challenges the necessity of bismuth-containing regimens as the default standard. The favorable pharmacokinetics and tolerability profile of VPZ align with the demands of contemporary clinical practice, where ease of use, adherence, and resistance mitigation are paramount. Future research should focus on tailoring VPZ-based therapy to resistance profiles in other geographical areas where comparative trials against standard-of-care treatment are scarce or missing, assessing long-term outcomes, and integrating these findings into national and international treatment guidelines. Meanwhile, clinicians should consider VPZ triple therapy as a viable, evidence-based alternative to traditional quadruple regimens, offering patients a shorter, simpler, and highly effective route to H. pylori eradication.

ACKNOWLEDGEMENTS

The authors would like to thank Lubnin A for his valuable assistance with literature search and retrieval, which greatly supported the preparation of this manuscript.